DESCRIPTION OF OVERALL CENTER (provided by applicant): The overall goal of the Yale Interdisciplinary Center for Polycystic Kidney Disease Research is to elucidate the mechanisms by which defects in the polycystin genes result in autosomal dominant polycystic kidney disease (ADPKD) and to understand the factors that modify the expression of the disease phenotype. Studies performed during the first 5 years of this Center Grant have provided the foundation for our present understanding of the importance of PC-1/PC-2 interactions in suppressing cyst formation, established a central role of the cilia in multiple forms of cystic disease, and have promoted novel concepts about how polycystins are processed and traffic in the cell. In the renewal of this award, these results have been utilized to focus the research on the areas of regulated post-translational modification and trafficking of polycystins, as well as their role in ciliary function and signaling. To investigate this hypothesis, Project by Somlo will define how PC-1 and PC-2 traffic to cilia, and will identify the domains within these proteins that mediate trafficking and determine whether graded interruption of this process can directly promote cystogenesis in animal models. Project by Caplan will explore the role of signaling by the cleaved C-terminal domain of PC-1, and how this is regulated by PC-2. Project by Sun has utilized the power of zebrafish genetic screening to identify a unique ciliary protein that mimics many of the aspects of PKD in the zebrafish model and will explore the role of this protein in normal ciliary function. Project by Cantley will investigate the role of polycystin signaling in regulating the morphogenic events that mediate tubule formation, and will explore the ability of Ngal to modify these signals and thereby suppress cyst formation in vivo. Project by Ehrlich will utilize expertise in calcium channel signaling to define how PC-2 calcium channel activity is regulated in the cilia. These efforts will be supported by the Mouse and Cell Line Core that has an exceptional array of in vivo animal and cell-based models of polycystin function and ADPKD. We believe that these projects, by addressing the central hypothesis from different directions focused by the expertise of each investigator, will lead to substantial progress in understanding the pathogenesis of cyst formation in ADPKD, and will lay the groundwork for the establishment of clinical trials for suppressing cyst progression in patients with this disease.